Fenofibrate reduces systemic inflammation markers independent of its effects on lipid and glucose metabolism in patients with the metabolic syndrome

J Clin Endocrinol Metab. 2010 Feb;95(2):829-36. doi: 10.1210/jc.2009-1487. Epub 2010 Jan 8.


Context: Fenofibrate is a peroxisome proliferator-activated receptor alpha agonist widely used in clinical practice, but its mechanism of action is incompletely understood.

Objective: The aim of the study was to assess whether improvement in subclinical inflammation or glucose metabolism contributes to its antiatherogenic effects in insulin-resistant subjects with the metabolic syndrome (MetS).

Design and setting: We conducted a randomized, double-blind, placebo-controlled study in the research unit at an academic center.

Patients: We studied 25 nondiabetic insulin-resistant MetS subjects.

Intervention(s): We administered fenofibrate (200 mg/d) and placebo for 12 wk.

Main outcome measures: Before and after treatment, we measured plasma lipids/apolipoproteins, inflammatory markers (high-sensitivity C-reactive protein, IL-6, intercellular adhesion molecule/vascular cell adhesion molecule), adipocytokines (adiponectin, TNFalpha, leptin), and insulin secretion (oral glucose tolerance test). We also assessed adipose tissue, hepatic and peripheral (muscle) insulin resistance fasting and during a euglycemic insulin clamp with (3)H glucose and (14)C palmitate infusion combined with indirect calorimetry.

Results: Subjects displayed severe insulin resistance and systemic inflammation. Fenofibrate significantly reduced plasma triglyceride, apolipoprotein (apo) CII, apo CIII, and apo E (all P < 0.01), with a modest increase in high-density lipoprotein-cholesterol (+12%; P = 0.06). Fenofibrate markedly decreased plasma high-sensitivity C-reactive protein by 49.5 +/- 8% (P = 0.005) and IL-6 by 29.8 +/- 7% (P = 0.03) vs. placebo. However, neither insulin secretion nor adipose tissue, hepatic or muscle insulin sensitivity or glucose/lipid oxidation improved with treatment. Adiponectin and TNF-alpha levels were also unchanged. Improvement in plasma markers of vascular/systemic inflammation was dissociated from changes in triglyceride/high-density lipoprotein-cholesterol, apo CII/CIII, or free fatty acid concentrations or insulin secretion/insulin sensitivity.

Conclusions: In subjects with the MetS, fenofibrate reduces systemic inflammation independent of improvements in lipoprotein metabolism and without changing insulin sensitivity. This suggests a direct peroxisome proliferator-activated receptor alpha-mediated effect of fenofibrate on inflammatory pathways, which may be important for the prevention of CVD in high-risk patients.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • C-Reactive Protein / analysis*
  • Double-Blind Method
  • Fatty Acids, Nonesterified / blood
  • Female
  • Fenofibrate / pharmacology*
  • Glucose / metabolism*
  • Humans
  • Hypolipidemic Agents / pharmacology*
  • Insulin Resistance
  • Interleukin-6 / blood*
  • Lipid Metabolism / drug effects*
  • Lipolysis / drug effects
  • Liver / metabolism
  • Male
  • Metabolic Syndrome / drug therapy*
  • Metabolic Syndrome / metabolism
  • Middle Aged
  • Muscle, Skeletal / metabolism
  • PPAR alpha / physiology


  • Fatty Acids, Nonesterified
  • Hypolipidemic Agents
  • Interleukin-6
  • PPAR alpha
  • C-Reactive Protein
  • Glucose
  • Fenofibrate